EP3810097A1 - Forme posologique comprenant un produit biothérapeutique vivant - Google Patents

Forme posologique comprenant un produit biothérapeutique vivant

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Publication number
EP3810097A1
EP3810097A1 EP19734469.0A EP19734469A EP3810097A1 EP 3810097 A1 EP3810097 A1 EP 3810097A1 EP 19734469 A EP19734469 A EP 19734469A EP 3810097 A1 EP3810097 A1 EP 3810097A1
Authority
EP
European Patent Office
Prior art keywords
dosage form
live
capsule
bacteria
cfu
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19734469.0A
Other languages
German (de)
English (en)
Inventor
Christophe Carite
Sophie Declomesnil
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CJ Bioscience Inc
Original Assignee
4D Pharma Research Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB1810061.0A external-priority patent/GB201810061D0/en
Priority claimed from GBGB1818740.1A external-priority patent/GB201818740D0/en
Application filed by 4D Pharma Research Ltd filed Critical 4D Pharma Research Ltd
Publication of EP3810097A1 publication Critical patent/EP3810097A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to pharmaceutical products comprising a live biotherapeutic product.
  • the invention also relates to processes for manufacturing such pharmaceutical products and kits comprising such products.
  • the human intestine is thought to be sterile in utero, but it is exposed to a large variety of maternal and environmental microbes immediately after birth. Thereafter, a dynamic period of microbial colonization and succession occurs, which is influenced by factors such as delivery mode, environment, diet and host genotype, all of which impact upon the composition of the gut microbiota, particularly during early life. Subsequently, the microbiota stabilizes and becomes adult-like.
  • the human gut microbiota contains more than 500-1000 different phylotypes belonging essentially to two major bacterial divisions, the Bacteroidetes and the Firmicutes.
  • the successful symbiotic relationships arising from bacterial colonization of the human gut have yielded a wide variety of metabolic, structural, protective and other beneficial functions.
  • the enhanced metabolic activities of the colonized gut ensure that otherwise indigestible dietary components are degraded with release of by-products providing an important nutrient source for the host.
  • the immunological importance of the gut microbiota is well-recognized and is exemplified in germfree animals which have an impaired immune system that is functionally reconstituted following the introduction of commensal bacteria. Dramatic changes in microbiota composition have been documented in gastrointestinal disorders such as inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • Clostridium cluster XlVa bacteria are reduced in I BD patients whilst numbers of E. coli are increased, suggesting a shift in the balance of symbionts and pathobionts within the gut.
  • this microbial dysbiosis is also associated with imbalances in T effector cell populations.
  • LBP Live Biotherapeutic Products
  • LBP are defined as biological products that: 1) contain live organisms, such as bacteria; 2) are applicable to the prevention, treatment, or cure of a disease or condition of human beings; and 3) are not vaccines. It is further stated in the FDA's guidance document that (unlike probiotic products) LBP are subjected to the same rigorous scrutiny as pharmaceutical agents by regulatory bodies.
  • LBP LBP provide exciting and innovative therapies for a range of disease states, they remain challenging to formulate such that the active principles are viably delivered to the patient, especially after prolonged periods of storage prior to administration.
  • APIs active pharmaceutical ingredients
  • proton pump inhibitors such as omeprazole, esomeprazole and pantoprazole or b) causing an irritant effect to the stomach, for example aspirin.
  • the skilled addressee will also be aware of formulation approaches to enable such APIs to be reliably delivered to the intestine even after prolonged periods of storage.
  • One such approach is to formulate the API in enterically coated tablets, i.e. in tablet cores which are coated with one or more layers of gastroresistant material.
  • enteric coating material When such tablets are orally administered to patients, the enteric coating material is not dissolved in the acidic medium of the stomach and thus release of the API contained in the stomach is prevented. However, once the tablets pass into the intestine and encounter the less acidic medium there, dissolution of the coating occurs and the API is released.
  • pH-dependent coatings which dissolve and release API contained within when the coating is exposed to a medium having a specific pH .
  • the Eudragit ® range of enteric polymers dissolve at pH 5.5 or above (for the L 30 D-55 and L 100-55 grades), at pH 6.0 or a bove (for the L 100 and L 12,5 grades) and above pH 7.0 (for the S 100, S 12,5 and FS 30 D grades).
  • These polymers are typically supplied as solutions or dispersions which can be used to coat tablet cores, or as powders which can be made up into solutions or dispersions by the tablet manufacturer and then used to coat the tablet cores.
  • An alternative, albeit related formulation approach for preparing APIs for intestinal delivery is to provide a formulation in a capsule, for example a soft or hard gelatin capsule, and then coat the capsule with enteric polymers such as those discussed above. Additionally, to prevent the inadvertent egress of API from the coated capsule, it is common practice to additionally band capsules formed of two pieces to securely seal the capsule. While such approaches have been successfully employed to formulate certain APIs for intestinal delivery on a commercial scale, it has been found that they are not necessarily applicable to more sensitive APIs, particularly LBP. The present disclosure recognizes that one of the main reasons for this difficulty in formulating a viable product is the harsh conditions to which the live bacteria are subjected. In many LBP or probiotic formulations, the bacteria are provided in lyophilised form. This is achieved by freeze-drying, a process in which low temperatures and pressures are used to provide a dry, powdered product and the exposure of bacterial populations to such conditions results in a loss in viable organisms.
  • the obtained powder is blended with excipients.
  • Shear forces exerted by the mixing apparatus can inactivate bacteria.
  • the presence of oxygen in mixing apparatus can also cause viable cell loss.
  • the LBP for some applications, it is desirable to deliver the LBP to the intestine.
  • this can be achieved through the use of gastro-resistant coating/s, e.g. to tablet cores or to conventional capsules containing the LBP. It has been found that this step significantly adversely affects bacterial viability in some embodiments. Without wishing to be bound by theory, it is contemplated in the present disclosure that this is due to ingress of solvent/s used during application of the enteric coating into the interior of the dosage form (e.g. the tablet core or the interior of the capsule) which kill the live bacteria and / or exposure of the products to elevated temperatures during drying of the coating.
  • the present disclosure also recognizes that, once formulated, risks to the viability of the bacterial population still exist. Prior to administration of the dosage form, it can be stored for months if not years prior to administration. Over time, subtle changes to the formulation can adversely affect the viable cell count, for example the take up of atmospheric moisture, or excipient incompatibility with the LBP, and these issues may only become apparent over prolonged periods.
  • the present disclosure recognizes that the administration of the formulated product can also reduce viable cell count.
  • the products Once ingested, the products encounter a highly acidic environment in the stomach before they reach the intestine. Formulating the products to protect the bacteria from the gastric environment in order to survive this stage in sufficient numbers can provide a significant therapeutic benefit as compared to a the corresponding bacteria found in nature.
  • one approach to enhance the gastro-resistance of APIs provided in enterically coated capsules is to band the capsules.
  • banding processes (which require the use of solvents and / or elevated temperatures for drying) have now been linked to reductions in bacterial viability.
  • LBP lactobacillus spp
  • Bacillus spp such as B. clausii
  • LBP lactobacillus spp
  • B. clausii protective spores
  • One further difficulty of formulating LBP is that many therapeutically active organisms are anaerobic and the exposure of those organisms to air, either during the preparation of the products, or during storage (e.g. from ingress of air into the interior of products containing those organisms) is problematic and can result in a reduction of viable cell count.
  • an orally administrable enteric dosage form comprising a live biotherapeutic product which i) comprises an antioxidant, wherein the antioxidant is cysteine, ii) does not comprise sodium carbonate or calcium carbonate, and / or iii) does not comprise maltodextrin.
  • shelf stable is used to mean that when the dosage form is stored at least 12 months in moisture-proof packaging at a temperature of 2°C to 8°C, the viable cell count of the dosage form (CFU count per gram, excluding capsule shell (if present) or enteric coating (if present)) decreases by no more than 3 log.
  • the viable cell count of the dosage form decreases by no more than 2 log when the dosage form is stored at least 12 months in moisture-proof packaging at a temperature of 2°C to 8°C, and in certain other embodiments, the viable cell count of the dosage form decreases by no more than 1 log when the dosage form is stored at least 12 months in moisture-proof packaging at a temperature of 2°C to 8°C. In embodiments of the invention, the viable cell count of the dosage form, when stored at 6 months in moisture-proof packaging at a temperature of 5°C decreases by no more than 3 log.
  • the viable cell count of the dosage form decreases by no more than 2 log over 6 months storatge, in certain other embodiments, the viable cell count of the dosage form decreases by no more than 1 log over 6 months storage. In certain other embodiments, the viable cell count of the dosage form decreases by no more than 0.5 log over 6 months storage. In certain other embodiments, the viable cell count of the dosage form decreases by no more than 1 log over 21 months storage.
  • antioxidants are known to those of skill in the art of pharmaceutical formulation.
  • the inventors have advantageously found that, as demonstrated in the examples which follow, cysteine outperforms conventionally used antioxidants such as ascorbic acid in maintaining a viable cell count of the therapeutically active bacteria.
  • antioxidants in addition to cysteine can be employed.
  • These include arginine, ascorbic acid (and salts and esters thereof e.g. ascorbyl palmitate, sodium ascorbate), butylated agents such as butylated hydroxyanisole or butylated hydroxytoluene, citric acid, erythorbic acid, fumaric acid, glutamic acid, glutathione, malic acid, methionine, monothioglycerol, pentetic acid, metabisulfite (such as sodium metabisulfite, potassium metabisulfite), propionic acid, propyl gallate, uric acid, sodium formaldehyde sulfoxylate, sulphite (e.g. sodium sulphite), sodium thiosulfate, sulphur dioxide, thymol, tocopherol (free or esterified) uric acid (and salts thereof) and salts and / or esters thereof.
  • arginine as
  • cysteine has been considered as an antioxidant in the formulation of certain pharmaceutical products, its use in the formulation of dosage forms comprising LBP is not known.
  • the finding that cysteine can contribute to the long-term stabilisation of LBP is surprising given that cysteine has been known for many years to exhibit bacteriocidal effects.
  • Berglin et ai Journal of Bacteriology, October 1982, 152(1), 81-8
  • cysteine does not exert its bacteriostatic effects on LBP, and (as mentioned above) actually enhances stability of the dosage forms of the invention.
  • Feature ii) of the present invention is a further formulation approach which the inventors have unexpectedly identified as contributing to product stability permitting the delivery to patients of pharmaceutically acceptable levels of LBP.
  • a range of gas-evolving excipients have conventionally been used in the formulation of LBP. I ndeed, the use of such excipients has been explicitly advocated in the scientific literature. For example, in a paper by Kim et al. (International Journal of Food Science and Technology 2017, 52, 519-530), the use of calcium carbonate as an encapsulant was advocated to enhance LBP survival under simulated gastric conditions and upon refrigerated storage. In Majkowska et al. (Polish Journal of Food and Nutrition
  • LBP products comprise gas-evolving excipients such as sodium or calcium carbonate.
  • gas-evolving excipients such as sodium or calcium carbonate.
  • examples of such products include Hyperbiotics' PRO-15, Guts & Glory's Probiotic Power 60 Capsules, American Health's Probiotic CD and Kyodophilus' Kyolic to name a few.
  • the dosage form of the invention does not comprise sodium carbonate and / or calcium carbonate.
  • the third feature of the present invention is also beneficial to the provision of shelf stable dosage forms comprising LBP as the inventors have found that maltodextrin can be incompatible with LBP.
  • the dosage form of the present invention is an orally administrable enteric dosage form, i.e. one which is capable of dissolution only in selective media (i.e. the intestinal environment) thus preventing release of its contents in the stomach.
  • a gastroprotective dosage form as described herein can comprise an effective amount of an LBP (i.e. a live anaerobic bacteria) and an antioxidant, where the effective amount of the LBP in colony forming units (CFU) decreases by no more than 1 log in a simulated gastric environment.
  • an LBP i.e. a live anaerobic bacteria
  • CFU colony forming units
  • Gastroprotective properties can be determined by, for example: (a) exposing a dosage form described herein to an acid media at pH 1.2 for 30 minutes, (b) exposing the dosage form to an intestinal medium at pH 6.8 for 45 minutes, and (c) comparing the CFU after the exposing relative to prior to the exposing.
  • enteric dosage forms include tablets, capsules, granules, and other micro- or nano-formulations, such as alginate encapsulated particles and in embodiments of the invention, the dosage form can be any of these. In some cases, enteric tablets or capsules are particularly preferred. The skilled person will also be familiar with techniques for rendering dosage forms enteric. This is typically achieved by the application of enteric coatings to dosage forms, such as tablets or capsules, and enterically coated dosage forms constitute embodiments of the present invention. Enteric coating materials which can be employed in the present invention include polymers which dissolve at pH 5.5 or above (e.g.
  • the dosage form of the invention comprises a capsule
  • the capsule in addition to being enterically coated, can also be banded to prevent the ingress of gastric medium at the join between the two capsule halves.
  • the dosage form can be an intrinsically enteric dosage form.
  • the inventors have found that the use of such dosage forms, particularly intrinsically enteric capsules, provides a highly effective and straightforward approach to viably formulating LBP.
  • the term 'intrinisically enteric capsule' is used to refer to a capsule which is formed (either partially or totally) from material which dissolves when exposed to medium having a mildy acidic, neutral or basic pH, thus releasing the contents of the capsule into the medium.
  • the intrinsically enteric capsule releases its contents when exposed to media having a pH of about 4.0 or above, about 4.5 or above, about 5.0 or above, about 5.5 or above, about 6.0 or above, about 6.5 or above or about 7.0 or above.
  • the term 'enteric' is used to refer to a material which dissolves upon exposure to media having a pH of about 4.0 or above, about 4.5 or above, about 5.0 or above, about 5.5 or above, about 6.0 or above, about 6.5 or above or about 7.0 or above.
  • the capsule does not require post-fill processing that could otherwise be potentially damaging to the LBP, for example, coating, drying and / or banding.
  • the intrinisically enteric capsule does not comprise a continuous coating (i.e. one that covers the entirety of the capsule) and / or is unbanded.
  • the intrinsically enteric capsule can be single layered or multi-layered and / or be wholly or partly formed of gastrointestinal material which dissolves at the specific pH .
  • one or more of the layers can be formed of enteric material which dissolves at the specific pH.
  • the intrinisically enteric capsule can be formed of any material/s which permit the total or partial dissolution of the capsule when exposed to medium having a mildy acidic, neutral or basic pH.
  • the intrinsically enteric capsule ca n be formed partially or totally from fatty acids, waxes, shellac, plastics, plant fibers, enteric polymers or mixtures thereof.
  • Enteric materials which can be employed in the present invention include, but are not limited to methacrylate polymers, methyl acrylate-methacrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers, polyvinyl acetate phthalate, shellac, sodium alginate, zein, dextrins, amylose starch and starch derivatives, and cellulose and cellulose derivatives including hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate, cellulose acetate succinate, cellulose acetate trimellitate, cellulose acetate phthalate, or mixtures thereof.
  • Plasticisers ca n also be comprised in the material from which the intrinsically enteric capsule is formed. Examples of materials that can be used in the production of intrinsically enteric capsules as well as methods for preparing such capsules are provided in European
  • Patent No. 2722104 the contents of which are incorporated herein by reference.
  • An example of an intrinsically enteric capsule is provided by Capsugel under the trade names enTRinsic DDT or ECDDT.
  • the capsules employed in the present invention can take any shape, form or construction provided that they can be closed to provide an enteric seal around the LBP comprised therein.
  • the capsules can be hard or soft.
  • the capsule is a two part capsule or a multi part capsule (i.e. a capsule closed by coupling more than two parts).
  • the capsule parts can be closed by mechanically coupling the two or more parts of the capsule. Any form of mechanical interaction which results in the formation of a seal around the LBP can be employed. Examples of mechanical interaction that are envisaged include push-fit coupling, friction coupling and / or threaded coupling.
  • live biotherapeutic product or “LBP” refers to a product that comprises live bacteria and is efficacious in the prevention, treatment or cure of a disease or condition, and is not a vaccine.
  • the LBP consists of or comprises anaerobic bacteria.
  • the LBP comprises or consists of bacteria which are obligate anaerobes.
  • the formulation of anaerobic bacteria is particularly challenging using conventional enteric formulation approaches. However, the inventors have found that such organisms can be viably formulated according to the present invention.
  • bacteria which can be formulated in accordance with the present invention can be hydrogenotrophic.
  • Organisms that can be formulated in accordance with the present invention include those belonging to the following genera: Enterococcus (e.g Enterococcus gallinarum, Enterococcus caselliflavus, Enterococcus faecalis, or Enterococcus faecium), Blautia (e.g. Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Blautia coccoides or Blautia producta), Bacteroides (e.g.
  • Pediococcus acidilacticii Eubacterium (e.g. Eubacterium contortum, fissicatena, Eubacterium eligens, Eubacterium hadrum, Eubacterium hallii, or Eubacterium rectale), Ruminococcus (e.g. Ruminococcus torques, Ruminococcus gnavus, or Ruminococcus bromii), Pseudoflavonifractor (e.g. Pseudoflavonifractor capillosus), Clostridium (e.g.
  • Clostridium nexile Clostridium hylemonae, Clostridium butyricum, Clostridium tertium, Clostridium disporicum, Clostridium bifermentans, Clostridium inocuum, Clostridium mayombei, Clostridium bolteae, Clostridium bartletti, Clostridium symbiosum or Clostridium orbiscindens), or Coprococcus (e.g. Coprococcus comes, or Coprococcus cattus).
  • Bifidobacterium e.g. Bifidobacterium breve.
  • Bifidobacterium adolescentis or Bifidobacterium longum include Acetivibrio (e.g. Acetovibrio ethanolgignens), Dorea (e.g. Dorea longicatena) or Lachnospiraceae.
  • Acetivibrio e.g. Acetovibrio ethanolgignens
  • Dorea e.g. Dorea longicatena
  • Lachnospiraceae examples include those disclosed in European Patent Nos. 1280541, 1448995, and 3209310, European Patent Publication No. 3206700, 2763685 and UK Patent Application No. 1423084.1, the contents of which are all incorporated herein by reference. Further examples of organisms that can be formulated according to the present invention include those disclosed in UK Patent Application Nos.
  • the dosage form does not comprise organisms belonging to Clostridium clusters IV or XIVa.
  • the LBP are not conventional probiotic bacteria, e.g. they do not belong to the genera Lactobacillus, Bifidobacterium and / or are not lactic acid bacteria.
  • the LBP can comprise or consist of obligate anaerobic bacteria. In other embodiments, the LBP can comprise or consist of facultative anaerobic bacteria and / or microaerophilic bacteria. In an exemplary embodiment, the LBP comprises or consists of non-sporulating bacteria.
  • the dosage forms of the invention comprise one or more bacterial strains of a specific genus and do not contain bacteria from any other genera, or which comprise only de minimis or biologically irrelevant amounts of bacteria from another genera.
  • the dosage forms of the invention comprise one or more bacterial strains of a specific species and do not contain bacteria from any other species, or which comprise only de minimis or biologically irrelevant amounts of bacteria from another species.
  • the dosage forms of the invention contain a single bacterial strain or species and do not contain any other bacterial strains or species. Such dosage forms can comprise only de minimis or biologically irrelevant amounts of other bacterial strains or species.
  • the dosage forms of the invention comprise more than one bacterial strain.
  • the dosage forms of the invention comprise more than one strain from within the same species (e.g. more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40 or 45 strains), and, optionally, do not contain bacteria from any other species.
  • the dosage forms of the invention comprise less than 50 strains from within the same species (e.g. less than 45, 40, 35, 30, 25, 20, 15, 12, 10, 9, 8, 7, 6, 5, 4 or 3 strains), and, optionally, do not contain bacteria from any other species.
  • the dosage forms of the invention comprise 1-40, 1-30, 1-20, 1- 19, 1-18, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-50, 2-40, 2-30, 2-20, 2-15, 2-10, 2-5, 6-30, 6-15, 16-25, or 31-50 strains from within the same species and, optionally, do not contain bacteria from any other species.
  • the invention comprises any combination of the foregoing.
  • the dosage form comprises a microbial consortium.
  • the dosage form comprises a specific bacterial strain as part of a microbial consortium.
  • the dosage form comprises a bacterial strain which is present in combination with one or more (e.g. at least 2, 3, 4, 5, 10, 15 or 20) other bacterial strains from other genera with which it can live symbiotically in vivo in the intestine.
  • the dosage form comprises a specific bacterial strain in combination with a bacterial strain from a different genus.
  • the microbial consortium comprises two or more bacterial strains obtained from a faeces sample of a single organism, e.g. a human.
  • the microbial consortium is not found together in nature.
  • the microbial consortium comprises bacterial strains obtained from faeces samples of at least two different organisms.
  • the two different organisms are from the same species, e.g. two different humans.
  • the two different organisms are an infant human and an adult human.
  • the two different organisms are a human and a non human mammal.
  • the invention provides the above pharmaceutical dosage form, wherein the amount of the bacterial strain is from about 1 x 10 3 to about 1 x 10 11 colony forming units per gram with respect to a weight of the dosage form (excluding the capsule body (if present) and any enteric coating (if present).
  • the pharmaceutical dosage form disclosed herein comprises one or more pharmaceutically acceptable excipients.
  • exemplary pharmaceutically acceptable excipients for the purposes of pharmaceutical compositions disclosed herein include, but are not limited to, binders, disintegrants, superdisintegrants, lubricants, diluents, fillers, flavors, glidants, sorbents, solubilizers, chelating agents, emulsifiers, thickening agents, dispersants, stabilizers, suspending agents, adsorbents, granulating agents, preservatives, buffers, coloring agents and sweeteners or combinations thereof.
  • binders include microcrystalline cellulose, hydroxypropyl methylcellulose, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinylpolypyrrolidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium, ceratonia, chitosan, cottonseed oil, dextrates, dextrin, ethylcellulose, gelatin, glucose, glyceryl behenate, galactomannan polysaccharide, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene glycol, polyethylene oxide, polymethacrylates, sodium alginate, sorbitol, starch, sucrose, sunflower oil, vegetable oil, tocofersolan, zein, or combinations thereof.
  • disintegrants examples include hydroxypropyl methylcellulose (HPMC), low substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium, sodium starch glycolate, lactose, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, starch, or combinations thereof.
  • HPMC hydroxypropyl methylcellulose
  • L-HPC low substituted hydroxypropyl cellulose
  • croscarmellose sodium sodium starch glycolate
  • lactose lactose
  • magnesium aluminum silicate magnesium aluminum silicate
  • methylcellulose polacrilin potassium
  • sodium alginate starch, or combinations thereof.
  • Examples of a lubricant include stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, glycerin monostearate, glyceryl palmitostearate, magnesium lauryl sulfate, mineral oil, palmitic acid, myristic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, talc, zinc stearate, potassium benzoate, magnesium stearate or combinations thereof.
  • diluents include talc, ammonium alginate, calcium carbonate, calcium lactate, calcium phosphate, calcium silicate, calcium sulfate, cellulose, cellulose acetate, corn starch, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, microcrystalline cellulose, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sulfobutylether b-cyclodextrin, tragacanth, trehalose, xylitol, or combinations thereof.
  • Various useful fillers or diluents include, but are not limited to calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, silicified microcrystailine cellulose, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, fructose, kaolin, lactitol, lactose, lactose monohydrate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, microcrystailine cellulose, polydextrose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, trehalose and xylitol, or mixtures thereof.
  • Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, glyceryl behenate, polyethylene glycol, polyethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, and others as known in the art.
  • a lubricant is magnesium stearate.
  • glidants include, but are not limited to, tribasic calcium phosphate, calcium silicate, cellulose, powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch and talc, or mixtures thereof.
  • Pharmaceutically acceptable surfactants include, but are limited to both non-ionic and ionic surfactants suitable for use in pharmaceutical dosage forms. Ionic surfactants may include one or more of anionic, cationic or zwitterionic surfactants.
  • Various useful surfactants include, but are not limited to, sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of olyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearyic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, and poloxamer.
  • the invention provides the above pharmaceutical composition, wherein said bacterial strain is lyophilised. In some cases, the bacterial strain is lyophilised in a process in which the bacterial strain is not exposed to temperatures greater than about 100°C, greater than about 70°C, greater than about 50°C or greater than about 30°C.
  • the invention provides the above pharmaceutical composition, wherein when the composition is stored in a moisture tight container at 2°C to 8°C and the container is placed in an atmosphere having 50% relative humidity, the loss of the bacterial strain as measured in colony forming units (CFU) per gram is no greater than 3 log, no greater than 2 log or no greater than 1 log after a period of at least about 1 year, 1.5 years, 2 years, 2.5 years or 3 years.
  • CFU colony forming units
  • the composition when stored in a moisture tight container at 5°C and the container is placed in an atmosphere having 50% relative humidity, the loss of the bacterial strain as measured in colony forming units (CFU) per gram is no greater than 3 log, no greater than 2 log, no greater than 1 log or no greater than 0.5 log after a period of 6 months.
  • CFU colony forming units
  • the dosage form contains the LBP in an amount of from about l x 10 3 to about 1 x 10 13 CFU/g, respect to the weight of the dosage form (excluding the capsule body (if present) and any enteric coating (if present), for example, from about 1 x 10 4 to about 1 x 10 12 CFU/g, from about 1 x 10 6 to about 1 x 10 11 CFU/g, from about 1 x 10 s to about 1 x 10 12 ,or from about 1 x 10 8 to about 1 x 10 10 CFU/g.
  • the dosage form can comprise at least 1 x 10 10 CFU/g, at least 1 x 10 9 CFU/g, at least 1 x 10 8 CFU/g, at least 1 x 10 7 CFU/g, or at least 1 x 10 6 CFU/g.
  • the products of the present invention surprisingly maintain high levels of LBP viability following exposure to acidic media.
  • the cell count of LBP contained within the products of the present invention following exposure to a simulated gastrointestinal environment, namely a first medium having a pH of 1.2 for 30 minutes at 50 rpm paddle stirring followed by exposure to a second medium having a pH of 6.8 for 45 minutes at 120 rpm paddle stirring results in a reduction in viable cell count of 3 log or less, 2 log or less, or 1 log or less.
  • LBP viable cell count (e.g. to determine CFU/g) can be conducted using techniques known to those skilled in the art.
  • the CFU enumeration method can be carried out on lyophilised LBP.
  • the number of colony forming units per gram of composition present in the dosage form i.e. excluding the capsule shell (if present) and enteric coating (if present) is determined.
  • the LBP present in the dosage form can be commensal, i.e. it is obtained from a donor (e.g. a human infant, child, adolescent or adult).
  • the dosage form comprises a biologically pure single strain of bacteria.
  • biologically pure refers to a culture that comprises de minimis or biologically irrelevant levels of other strains of bacteria.
  • the dosage form comprises less than about 1%, less than about 0.5%, less than about 0.2%, less than about 0.1%, less than about 0.05%, less than about 0.02% or less than about 0.01% as a proportion of the total number of bacterial cells of other bacterial species.
  • the dosage form of the invention can comprise a plurality, e.g. 2, 3, 4, 5 or more than 5 strains of bacteria.
  • the pharmaceutical products of the present invention can comprise one or more excipients including, for example diluents, stabilisers, growth stimulators, fillers, lubricants, glidants and the like.
  • the dosage forms of the invention can comprise one or more pharmaceutically acceptable excipients.
  • suitable excipients can be found in the Handbook of Pharmaceutical Excipients. Acceptable excipients for therapeutic use are well known in the pharmaceutical art.
  • Suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like.
  • Suitable diluents include ethanol, glycerol and water.
  • the choice of pharmaceutical carrier, excipient or diluent can be selected with regard to standard pharmaceutical practice.
  • the dosage forms can comprise any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).
  • Suitable binders include starch, gelatine, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.
  • Suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Preservatives, stabilizers, dyes and even flavouring agents can be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p- hydroxybenzoic acid.
  • Suspending agents can be also used.
  • the LBP is not microencapsulated.
  • the product of the present invention can comprise a sugar for example a monosaccharide or disaccharide. Additionally or alternatively, the sugar can be a reducing sugar or non-reducing sugar. In such embodiments, where the products comprise a reducing sugar, non-reducing sugars can be excluded from the product, and vice versa. Examples of specific sugars that can be employed as excipients in the present invention include sucrose and trehalose.
  • the pharmaceutical products of the invention can further comprise a prebiotic.
  • prebiotic means a non-digestible ingredient that beneficially affects the LBP by selectively stimulating the growth and/or activity of one or a limited number of bacteria. Examples of prebiotics include oligosaccharides, fructooligosaccharides and galactooligosaccharides.
  • the LBP (and optionally one or more of any excipients that are present) can be provided in the form of a lyophilisate.
  • the lyophilizate can additionally comprise other excipients with which the LBP was lyophilised in order to protect the LBP during lyophilisation or to provide functional properties to the lyophilizate.
  • excipients that can be present in the lyophilizate these include mannitol, skim milk and bovine serum albumin (BSA), sucrose, trehalose and / or one of the other sugars identified above. A mixture of mannitol and sucrose as lyophilisation medium may be used.
  • the lyophilizate comprising the LBP can also comprise an antioxidant, (e.g.
  • cysteine or a salt thereof arginine, ascorbic acid (and salts and esters thereof e.g. ascorbyl palmitate, sodium ascorbate), butylated agents such as butylated hydroxyanisole or butylated hydroxytoluene, citric acid, erythorbic acid, fumaric acid, glutamic acid, glutathione, malic acid, methionine, monothioglycerol, pentetic acid, metabisulfite (such as sodium metabisulfite, potassium metabisulfite), propionic acid, propyl gallate, uric acid, sodium formaldehyde sulfoxylate, sulphite (e.g.
  • the remainder of the dosage form can be free of antioxidants.
  • An antioxidant employed in embodiments can be present as a salt.
  • salts can include acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bitartrate, bromide, butyrate, butyn- 1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate, hydroxybenzoate, g-hydroxybut
  • metaphosphate methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1- napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate, and xylenesulfonate.
  • the lyophilizate can be blended with additional excipients.
  • the dosage form comprises i) a lyophilizate comprising the LBP and ii) one or more additional excipients.
  • One or more of the additional excipients can also be provided in the lyophilizate.
  • the additional excipients can be any of the excipient disclosed herein, for example one or more of the antioxidants discussed herein, a carrier, diluent, binder, lubricant, suspending agent, coating agent, solubilising agent, stabiliser, growth stimulator, filler, lubricant and / or glidant.
  • the moisture content of the LBP in the dosage form of the invention is less than about lOOOOppm, less than about 5000ppm, less than about 2000ppm, less than about lOOOppm, less than about 500ppm, less than about 200ppm or less than about lOOppm.
  • the one or more excipients comprises an antioxidant, wherein the antioxidant is cysteine, ii) does not comprise sodium carbonate or calcium carbonate, and / or iii) does not comprise maltodextrin.
  • the live biotherapeutic product can be provided by lyophilising bacteria alone or in combination with one or more excipients to produce a lyophilizate.
  • the excipient/s provided in step i) of the process of the invention can be comprised in the lyophilizate, and / or be separate from the lyophilizate.
  • the use of intrinsically enteric capsules in combination with LBP is advantageous as the use of conventional enteric coating process steps which can adversely affect LBP viability can be avoided.
  • the closed intrinsically enteric capsule is not subjected to coating, drying and / or banding steps.
  • the LBP may not be exposed to a temperature greater than about 50°C, greater than about 40°C or greater than about 30°C during steps i), ii-a) and / or ii-b).
  • the LBP can comprise anaerobic bacteria. Accordingly, in the processes of the invention for preparing such products, steps i), ii-a) and / or ii-b) are operated in an inert (i.e. air-free) environment.
  • air-free environment is used here to mean an environment comprising less than about lOOOOppm, less than about 5000ppm, less than about 2000ppm, less than about lOOOppm, less than about 500ppm, less tha n about 200ppm or less than about lOOppm of oxygen.
  • an inert gas e.g. nitrogen.
  • the dosage forms of the invention can be presented in a packaging material which can contain one or more dosage forms.
  • the packaging material may, for example, comprise metal (e.g. aluminium) or plastic foil, such as a blister pack. Additionally, the products can be packaged in a bottle. Regardless of the specific type of packaging, the products of the present invention can be packaged in packaging material which is air and / or moisture impermeable containers. I n some embodiments, a packaging can include packaging under reduced pressure.
  • the pharmaceutical products are presented in the form of a kit comprising the products and instructions for use.
  • the instructions for use can include instructions to store the products at temperatures less than about 20°C, less than about 15°C, or less tha n about 10°C, for example under refrigeration, e.g. at a temperature of about 2 to 8°C.
  • the enteric coated capsule was then subjected to stimulated gastric conditions (1 hour at an acidic media at pH 1.2) and a cell count conducted.
  • the capsules ruptured, dispersing their contents into the acid medium.
  • a count of viable LBP cells in that medium was conducted and it was found that a significant loss (over 3 log relative to the cell count carried out upon encapsulation) had occurred.
  • Example 2 Storage Stability of Inventive Products Mannitol, cysteine hydrochloride and magnesium stearate were weighed and mixed together in a temperature controlled clean room. The obtained blend was then mixed with lyophilizate comprising Blautia hydrogenotrophica, mannitol, sucrose and cysteine in a blender housed in a containment module in an inert atmosphere, at a temperature of ⁇ 25°C and at a relative humidity of ⁇ 40%. The obtained blend was then filled into size 0 Enteric Capsule Drug Delivery Technology (ECDDT) capsules (Capsugel ® ) in the containment module with the obtained capsules then being packaged in moisture / air impermeable bags (PET/Alu/PA/PE).
  • ECDDT Enteric Capsule Drug Delivery Technology
  • the products were stored at 2 to 8°C and cell counts were conducted upon i) encapsulation, and ii) thirteen months following encapsulation.
  • the viable cell count was 1.3 x 10 11 while at thirteen months, the count was 6.6 x 10 10 .
  • the viable cell count per capsule was 4.7 x 10 10 upon encapsulation and 2.0 x 10 10 after 15 months of storage. No substantial loss in cell count ( ⁇ 1 log) was observed over periods in excess of 12 months demonstrating the storage stability of the products.
  • Example 3 Dissolution of Inventive Products
  • Dosage forms prepared in accordance with Example 2 were exposed to acidic media (pH 1.2) for 2 hours under paddle stirring in accordance with the US Pharmacoepia ⁇ 711>. No evidence of disintegration, rupture or content release of the capsules was observed. The products were then transferred to a simulated intestinal medium (pH 6.8) causing the capsules to rapidly disintegrate.
  • Dosage forms prepared in accordance with Example 2 were exposed to acidic media (pH 1.2) for 30 minutes using the paddle method. They were then transferred to a simulated intestinal medium (pH 6.8) for 45 minutes. The example was ran under inert atmosphere (continuous sparging with nitrogen). Exposure of the products to the simulated intestinal medium resulted in the complete release of the LBP from the capsule and a cell count was performed. No substantial loss in cell count ( ⁇ 1 log) was observed. A cell count was also performed on the acidic medium and no release of LBP was detected, confirming the gastroprotective effect of the dosage forms of the present invention.
  • Lyophilisate comprising Enterococcus gallinarum was prepared having the following compositions:
  • Cysteine-containing lyophilizate was then blended with an antioxidant-free excipient mixture and encapsulated within intrinsically enteric capsules.
  • the resulting dosage forms were then packaged in alu/alu blister packaging and stored for a twelve month period at a temperature of 2 to 8°C.
  • a count of viable cells was conducted on the dosage form i) following encapsulation, ii) twelve months after encapsulation and iii) twenty one months after encapsulation. Following encapsulation, a cell count of 1 x 10 11 CFU/g (7 x 10 10 per capsule) was observed. After 12 months of storage conditions, a count of 4 x 10 10 CFU/g (3 x 10 10 per capsule) was recorded. The CFU per capsule recorded after 21 months of storage was 3 x 10 10 ) This demonstrates that not only does the formulation protect LBP during lyophilisation, but it also permits a shelf-stable dosage form to be provided.

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Abstract

L'invention concerne une forme posologique entérique comprenant un produit biothérapeutique vivant.
EP19734469.0A 2018-06-19 2019-06-19 Forme posologique comprenant un produit biothérapeutique vivant Withdrawn EP3810097A1 (fr)

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